Challenges and considerations for reproducibility of STARR-seq assays

Das, Maitreya; Hossain, Ayaan; Banerjee, Deepro; Praul, Craig A.; Girirajan, Santhosh

doi:10.1101/gr.277204.122

Cited by 8 publications

(1 citation statement)

References 75 publications

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“…STARR-seq has been widely employed in genome-wide quantification of enhancer activities in different species and different types of cells (Das et al 2023). When applied to human and other mammalian cells (Liu et al 2017; Johnson et al 2018), due to the large size of their genomes, usually large fragment sizes have to be adopted if the whole genome is used as input, resulting in low-resolution enhancer sequences identified.…”

Section: Introductionmentioning

confidence: 99%

High-resolution dissection of human cell type-specific enhancers incisandtransactivities

Wang,

Yang,

2023

Preprint

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The spatiotemporal specific gene expression is regulated by cell type-specific regulatory elements including enhancers, silencers and insulators etc. The massively parallel reporter assay (MPRA) methods like STARR-seq facilitate the systematic study of DNA sequence intrinsic enhancer activities in a large scale. However, when applied to human cells, it remains challenging to identify and quantify cell type-specific active enhancers in the genome-wide scale with high-resolution, due to the large size of human genome. In this study, we selected the H3K4me1 associated dinucleosome with the linker DNA sequences as candidate enhancer sequences in two different human cell lines and performed ChIP-STARR-seq to quantify the cell type-specific enhancer activities with high-resolution in a genome-wide scale. Furthermore, we investigated how the activity landscape of enhancer repository would change when transferred from native cells (cis activity) to another cell lines (trans activity). Using ChIP-STARR-seq of the candidate enhancers in native cells and another type of cells, we obtained enhancers cis activity maps and trans activity maps in two different cell lines. The cis and trans activity maps enabled us to identify cell type-specific active enhancers, with enrichment of motifs of differentially expressed TFs. Comparisons between the cis and trans activity maps revealed general consistent regulatory property with different levels of activity in the two cell types, suggesting the sequence intrinsic regulatory properties keep similar in different type of cells. This study provides a new perspective of sequence intrinsic enhancer activities in different types of cells.

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Section: Introductionmentioning

confidence: 99%

High-resolution dissection of human cell type-specific enhancers incisandtransactivities

Wang,

Yang,

2023

Preprint

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Technological advancements in functional interpretation of genome‐wide association studies (GWAS) findings: bridging the gap to clinical translation

Aherrahrou,

Kaikkonen

2024

FEBS Letters

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A novel interpretable deep learning-based computational framework designed synthetic enhancers with broad cross-species activity

Li,

Zhang,

Peng

et al. 2024

Nucleic Acids Research

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Enhancers play a critical role in dynamically regulating spatial-temporal gene expression and establishing cell identity, underscoring the significance of designing them with specific properties for applications in biosynthetic engineering and gene therapy. Despite numerous high-throughput methods facilitating genome-wide enhancer identification, deciphering the sequence determinants of their activity remains challenging. Here, we present the DREAM (DNA cis-Regulatory Elements with controllable Activity design platforM) framework, a novel deep learning-based approach for synthetic enhancer design. Proficient in uncovering subtle and intricate patterns within extensive enhancer screening data, DREAM achieves cutting-edge sequence-based enhancer activity prediction and highlights critical sequence features implicating strong enhancer activity. Leveraging DREAM, we have engineered enhancers that surpass the potency of the strongest enhancer within the Drosophila genome by approximately 3.6-fold. Remarkably, these synthetic enhancers exhibited conserved functionality across species that have diverged more than billion years, indicating that DREAM was able to learn highly conserved enhancer regulatory grammar. Additionally, we designed silencers and cell line-specific enhancers using DREAM, demonstrating its versatility. Overall, our study not only introduces an interpretable approach for enhancer design but also lays out a general framework applicable to the design of other types of cis-regulatory elements.

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Challenges and considerations for reproducibility of STARR-seq assays

Cited by 8 publications

References 75 publications

High-resolution dissection of human cell type-specific enhancers incisandtransactivities

High-resolution dissection of human cell type-specific enhancers incisandtransactivities

Technological advancements in functional interpretation of genome‐wide association studies (GWAS) findings: bridging the gap to clinical translation

A novel interpretable deep learning-based computational framework designed synthetic enhancers with broad cross-species activity

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